The invention relates to the use of Factor H for the manufacture of a medicament to treat both chronic nephropathies which are not causally associated with proteinuria and chronic nephropathies which are causally associated with proteinuria. The invention also relates to large scale purification methods for Factor H.
The complement system comprising more than 40 different proteins directly or indirectly mediates attack and elimination of microbes, foreign particles and altered self cells via three different pathways of activation (alternative, lectin and classical pathway; Rother K et al. (Eds) The Complement System. 2nd revised edition, 1998; Springer Verlag). This process is highly restricted in terms of time and space and can discriminate between self (host cells) and foreign (e.g., microbes).
Some human diseases are obviously accompanied by an activation of these cascade-like activation pathways which is reflected by the occurrence of elevated levels of typical activation markers comprising the range from early to late components of the complement system, including inhibitor-protease complexes. Moreover, the sometimes observed cellular damage is taken as indicator of at least a local derailment of the complement system which usually is under tight control. From a quantitative point of view, proteolytic cleavage of C3 by specific C3 convertases plays a major role for complement activation. These convertases generate forms of C3b, which represent a potential component of new C3 convertase molecules, thereby stimulating the cascade.
The protection of self-cells and tissue is mediated by specific regulators or inhibitors, existing in the fluid-phase and/or in membrane-bound forms. These regulators include complement receptor 1 (CR1 or CD35: binds C3b and C4b, disassembles C3 convertases and permits C3b/C4b degradation by factor I), decay accelerating factor (DAF or CD55: binds C3b and disassembles C3/C5 convertase) and membrane co-factor protein (MCP or CD46: binds C3b and C4b to permit their degradation by factor I), which all are exclusively membrane-anchored proteins.
In addition to the membrane-anchored control proteins, the attachment of the soluble complement regulator Factor H (single-chain glycoprotein composed of 20 short consensus repeats, SCRs; 155 kDa; ˜9.3% carbohydrate) to the polyanionic surface of self cells represents a potent component for protection of the cell surface by increasing the inhibitory potential (JOzsi M et al.; Histol Histopathol 2004; 19:251-8). This protection is mainly achieved by efficiently reducing the lifetime of the alternative C3 convertase (C3bBb) by both binding to the covalently bound C3b and displacing Bb (decay acceleration), and catalysing the permanent inactivation of C3b via proteolytic cleavage by the serine proteinase Factor I (co-factor activity: generation of, e.g., iC3b, C3c; Rother K et al. (2nd revised edition) The Complement System. 1998, Springer Verlag; p. 28, 34-7). The activity of Factor H as co-factor for the protease factor I in the outer phase of the surface layer (approx. 20-140 nm) is facilitated by binding of Factor H to surface-located proteoglycans by means of the C-terminal SCR (JOzsi M et al.; Histol Histopathol 2004; 19:251-8). The protective potential of Factor H limits locally the progression of the complement cascade. This is of particular importance for cells which express a low number of the above mentioned membrane-anchored regulators, or for tissues which completely lack those endogenous control proteins, such as the kidney glomerular basement membrane (Hogasen K et al.; J Clin Invest 1995; 95:1054-61).
Patent EP 0 222 611 B1 comprises the use of Factor H in immune complex related diseases in which Factor H is only temporarily decreased, to downregulate complement activation, “Factor H and/or Factor I for use in the treatment of a vascular autoimmune disease”, “Factor H and/or Factor I for use in the treatment of systemic lupus erythematosus, rheumatoid arthritis or glomerulonephritis”, and “A process for preparing a pharmaceutical composition for use in the treatment of a vascular autoimmune disease comprising mixing Factor H and/or Factor I with a pharmaceutically acceptable carrier, diluent or adjuvant”. However, the scope of this patent is unequivocally related to glomerulonephritis as an immune complex (IC)-mediated nephropathy with glomerular deposition/formation of ICs generated outside or inside the kidney (e.g., Goodpasture-syndrom). In EP 0 222 611 B1 no teaching is comprised on the treatment of antibody-independent chronic nephropathies like, e.g., tubulointerstitial fibrosis (TIF), which specifies the formation of fibrous tissue within the space between the tubuli (interstitium).